An antibody targeting the N-terminal domain of SARS-CoV-2 disrupts the spike trimer
Naveenchandra Suryadevara, … , Ivelin S. Georgiev, James E. Crowe Jr.
Naveenchandra Suryadevara, … , Ivelin S. Georgiev, James E. Crowe Jr.
Published April 26, 2022
Citation Information: J Clin Invest. 2022;132(11):e159062. https://doi.org/10.1172/JCI159062.
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Research Article Immunology Virology

An antibody targeting the N-terminal domain of SARS-CoV-2 disrupts the spike trimer

Abstract

The protective human antibody response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) focuses on the spike (S) protein, which decorates the virion surface and mediates cell binding and entry. Most SARS-CoV-2 protective antibodies target the receptor-binding domain or a single dominant epitope (“supersite”) on the N-terminal domain (NTD). Using the single B cell technology called linking B cell receptor to antigen specificity through sequencing (LIBRA-Seq), we isolated a large panel of NTD-reactive and SARS-CoV-2–neutralizing antibodies from an individual who had recovered from COVID-19. We found that neutralizing antibodies against the NTD supersite were commonly encoded by the IGHV1-24 gene, forming a genetic cluster representing a public B cell clonotype. However, we also discovered a rare human antibody, COV2-3434, that recognizes a site of vulnerability on the SARS-CoV-2 S protein in the trimer interface (TI) and possesses a distinct class of functional activity. COV2-3434 disrupted the integrity of S protein trimers, inhibited the cell-to-cell spread of the virus in culture, and conferred protection in human angiotensin-converting enzyme 2–transgenic (ACE2-transgenic) mice against the SARS-CoV-2 challenge. This study provides insight into antibody targeting of the S protein TI region, suggesting this region may be a site of virus vulnerability.

Authors

Naveenchandra Suryadevara, Andrea R. Shiakolas, Laura A. VanBlargan, Elad Binshtein, Rita E. Chen, James Brett Case, Kevin J. Kramer, Erica C. Armstrong, Luke Myers, Andrew Trivette, Christopher Gainza, Rachel S. Nargi, Christopher N. Selverian, Edgar Davidson, Benjamin J. Doranz, Summer M. Diaz, Laura S. Handal, Robert H. Carnahan, Michael S. Diamond, Ivelin S. Georgiev, James E. Crowe Jr.

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Figure 2

Reactivity, functional, and genetic features of 102 human mAbs identified using LIBRA-Seq.

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Reactivity, functional, and genetic features of 102 human mAbs identifie...
(A) LIBRA-Seq scores for all cells for each experiment are shown as black circles for 3 different LIBRA-Seq runs. Antibodies that demonstrated either full or partial neutralization in the high-throughput RTCA assay are highlighted in green or purple, respectively. (B) mAb specificity or reactivity for each of the 4 S proteins or subdomains. The figure shows a heatmap for binding of 102 mAbs expressed recombinantly, representing OD values collected at 450 nm for each antigen (range, 0.5–4.0). White indicates a lack of detectable binding, blue indicates binding, and darker blue indicates higher OD values. To the right are the antibody numbers that demonstrated either full or partial neutralization in the high-throughput RTCA assay, highlighted in green or purple, respectively. (C) Genetic characteristics of mAbs that demonstrated either full or partial neutralization along with their ELISA reactivity; numbers in the boxes represent OD values collected at 450 nm (range, 0.5–4.0) and LIBRA-Seq scores for each antigen. White boxes indicate no or low reactivity, and red (ELISA) and purple (LIBRA-Seq) boxes represent reactivity for the respective antigens.